Both type 1 and type 2 diabetes are increasing in prevalence. Both are characterized by a loss of insulin secreting pancreatic beta cells. Type1 and Type 2 diabetes are both characterized by insulin resistance. Although this can be overcome by administering more insulin, insulin resistance in diabetes confers increased risk for heart disease, strokes and amputation. In the proposed studies, we will test the hypothesis that one of the reasons people with diabetes develops insulin resistance is because the pattern of insulin secretion is disturbed when the number of beta cells decreases below ~50% of normal. In health, almost all insulin is secreted in discrete insulin secretory bursts. In people with diabetes insufficient insulin is secreted because the size of the secretory bursts is too small. Once the number of beta cells drops below ~50% of normal, we postulate the size of the insulin pulses decreases as the remaining beta cells are unable to generate sufficient insulin to sustain these secretory bursts. However, we propose that this is not obvious because, at least initially, hepatic insulin clearance of insulin decreases as insulin secretion declines, so that the amount of circulating insulin remains relatively normal. So why does all this matter? It has long been appreciated that as people get close to developing diabetes (Impaired fasting glucose/glucose intolerance) this state is relatively unstable with rapid progression to diabetes. We propose that the reason underpinning this is that IFG/IGT imply in many cases that the beta cell mass has declined to ~50% of normal, pulsatile insulin secretion declines and as a consequence insulin resistance is increased. We suggest that the collective impact of this increment in insulin demand and decreased capacity to sustain insulin secretion leads to decompensation and onset of diabetes. If we are correct, then targeting the mechanisms subserving the decline in beta cell mass will be the most rationale approach to preventing type 1 and 2 diabetes. In the proposed studies, we will first examine humans with an ~50% pancreatectomy and those with IFG/IGT compared to controls for pulsatile insulin secretion and insulin sensitivity. Second we will directly establish the physiological role of pulsatile insulin secretion in vivo and finally we will examine the mechanism by which pulsatile insulin secretion enhances insulin signaling in target tissues. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a leading cause of premature death in the USA involving more than 20 million people. The present grant proposes continued funding of studied designed to establish the basis for the transition of patients from impaired fasting glucose to diabetes. If the basis of this transition was known it would be more realistic to establish strategies to prevent type 2 diabetes.